Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

Analysis of the mechanism(s) of immunological tolerance to a physiological soluble antigen in transgenic mice

grantor: University of TorontoThe mammalian immune system recognizes and responds to a vast array of foreign molecules, and its diversity is generated by V-(D)-J gene recombination during ontogeny. The central feature of the immune system is self-nonself discrimination, which results in immunological reactivity or tolerance (specific immunological hyporesponsiveness to a previously encountered antigen-Ag). Breakdown of self-tolerance may result in autoimmunity to the host's own self-Ags or tissues. Recent studies have demonstrated that both central (thymus-dependent) and peripheral (extra-thymic) tolerance can operate in an Ag-specific manner by at least two major mechanisms, namely, clonal deletion (physical elimination of autoreactive lymphocytes) and clonal anergy (functional inactivation of autoreactive lymphocytes). A third mechanism, active suppression (functional inhibition of autoreactive lymphocytes), may also be of relevance, particularly for peripheral tolerance. We previously characterized the T-cell receptor repertoire specific for different insulins in Balb/c mice and identified a minimal immunogenic peptide (A chain: 1-13). These results prompted us to establish a transgenic (Tg) mouse model to study the mechanism(s) of tolerance to a soluble self-Ag under physiological conditions in vivo. These mice express the gene for a foreign Ag (beef insulin, BI, mutated from human insulin genomic DNA) under the regulatory control of its own promoter so that the Tg product is expressed in pancreatic $\beta$-islet cells. In this Tg mouse model, the functional expression of BI (range: 10\sp{-10}-10\sp{-11}M) is regulated by the host's glucose/insulin homeostasis, and is associated with a differential activation of BI-specific Th1/Th2 cells in vivo. These Tg mice are hyporesponsive to BI immunization at the level of both humoral and cell-mediated immune responses, mediated by Ag-specific T cells. Despite the level of no detectable thymic expression of the Tg products, BI-specific hyporesponsiveness may still occur in mature thymocytes of the Tg mice, suggesting the operation of a thymic selection process to a peripheral soluble Ag. Exogenous IL-2 can restore responses in peripheral T cells in vitro, suggesting also the involvement of an "anergy-inducing" mechanism. Adoptive transfer of some BI-specific CD4\sp+ Th2 cells from Tg mice into normal syngeneic Balb/c mice induced Ag-specific hyporesponsiveness (as determined by BI-specific ELISA). This in turn suggests an active suppression mechanism may be involved in the maintenance of peripheral self-tolerance. Using a transwell coculture system, it seems that the cytokine TGF-$\beta$, not IL-4 or IL-10, may be involved in suppression (but not killing or apoptosis) of Ag-specific Th1 cells. This active suppression is exerted in a bystander (Ag-specific and effector-nonspecific) fashion in vivo, and is associated with self-tolerance. The work presented in this thesis significantly extends the earlier findings in other soluble-Ag Tg model systems in which one dominant mechanism has been reported to explain the tolerance observed. Our results suggest that, at least for soluble Ags expressed peripherally: (1) self-tolerance can be accomplished both intra- and extra-thymically, and (2) there are multiple levels of regulation for self-tolerance in vivo, operating in an Ag-specific fashion, including thymic selection, peripheral anergy and active suppression. These results provide clear and important information which contribute to our understanding of the basic mechanism(s) involved in self-nonself discrimination in biological tolerance. Application of this information should improve our understanding and treatment of various diseases associated with dysregulation of immune responses, including autoimmunity, transplantation and perhaps malignancy.Ph.D

Distinct cross talk of IL‐17 & TGF‐β with the immature CD11c+TRAF6(−/−)‐null myeloid dendritic cell‐derived osteoclast precursor (mDDOCp) may engage signaling toward an alternative pathway of osteoclastogenesis for arthritic bone loss in vivo

Abstract Background Dendritic cells (DCs), though borne heterogeneous, are the most potent antigen‐presenting cells, whose critical functions include triggering antigen‐specific naïve T‐cell responses and fine‐tuning the innate versus adaptive immunity at the osteo‐immune and/or mucosal mesenchyme interface. We previously reported that immature myeloid‐CD11c+DCs/mDCs may act like osteoclast (OC) precursors (OCp/mDDOCp) capable of developing into functional OCs via an alternative pathway of inflammation‐induced osteoclastogenesis; however, what are their contribution and signaling interactions with key osteotropic cytokines (i.e., interleukin‐17 [IL‐17] and transforming growth factor‐β [TGF‐β]) to bearing such inflammatory bone loss in vivo remain unclear to date. Methods Herein, we employed mature adult bone marrow‐reconstituted C57BL/6 TRAF6(−/−)‐null chimeras without the classical monocyte/macrophage (Mo/Mϕ)‐derived OCs to address their potential contribution to OCp/mDDOCp‐mediated osteoclastogenesis in the chicken type‐II‐collagen (CC‐II)‐induced joint inflammation versus arthritic bone loss and parallel associations with the double‐positive CD11c+TRAP+TRAF6‐null(−/−) DC‐like OCs detected in vivo via the quantitative dual‐immunohistochemistry and digital histomorphometry for analyses. Results The resulting findings revealed the unrecognized novel insight that (i) immature myeloid‐CD11c+TRAF6(−/−) TRAP+DC‐like OCs were involved, co‐localized, and strongly associated with joint inflammation and bone loss, independent of the Mo/Mϕ‐derived classical OCs, in CC‐II‐immunized TRAF6(−/−)‐null chimeras, and (ii) the osteotropic IL‐17 may engage distinct crosstalk with CD11c+mDCs/mDDOCp before developing the CD11c+TRAP+TRAF6(−/−)OCs via a TGF‐β‐dependent interaction toward inflammation‐induced arthritic bone loss in vivo. Conclusion These results confirm and substantiate the validity of TRAF6(−/−)‐null chimeras to address the significance of immature mCD11c+TRAP+DC‐like OCs/mDDOCp subset for an alternative pathway of arthritic bone loss in vivo. Such CD11c+mDCs/mDDOCp‐associated osteoclastogenesis through the step‐wise twist‐in‐turns osteo‐immune cross talks are thereby theme highlighted to depict a summative re‐visitation proposed

Dendritic cell-derived osteoclasts and inflammation-induced bone loss; development and regulation

Thesis (Ph. D.)--University of Rochester. School of Medicine and Dentistry. Dept. of Microbiology and Immunology, 2008.Inflammation-induced osteoclastogensis is a well established osteo-immunological phenomenon associated with dys-regulated bone remodeling, whereby the frequency and activity of osteoclasts (OC) become elevated under inflammatory conditions, in response to several stimuli including osteogenic cytokines signaling. OC are bone-resorbing cells, thus considered to be central players during inflammation-induced bone loss. They are derived from precursors of the monocyte/ macrophage lineage, in response to receptor activator of NF-κB ligand (RANKL) and macrophage-colony stimulating factor (M-CSF). Inflammation-induced osteoclastogenesis can lead to irreversible bone destruction and physical disability, and may be the result of several factors including infections, metabolic bone disorders, or autoimmunity. Dendritic cells (DC) are innate immune effectors, and as antigen presenting cells, they are critically involved in regulating adaptive immune responses, including T-cell immunity. Additionally, DC share common progenitors with OC and infiltrate bone adjacent tissues during inflammation, where their interactions with T-cells constitute a key component of the inflammatory infiltrate at active disease sites in human and experimental rheumatoid arthritis and periodontitis. The work presented in this thesis is focused on the characterization of DC-derived OC (DDOC) development and phenotype, and the identification of the osteogenic factors required and/or involved during the regulation of this process. Our findings suggest that DC can act as OC precursors under inflammatory conditions, therefore indicating a possible direct contribution by DC to inflammation-induced osteoclastogenesis. In the presence of Aggregatibacter actinomycetemcomitans sonicates (Aa) [previously Actinobacillus], or protein antigens, some DC subset(s) were found to up-regulate OC phenotype and function in a RANKL/RANK-dependent manner. Additional work investigated the in vivo relevance of DDOC phenomenon and examined the role of the anti-inflammatory cytokine transforming growth factor-beta (TGF-β) in the regulation of RANKL-dependent DDOC development, and found TGF-β to be important both in vitro and in vivo. Collectively, this thesis has studied DDOC development and regulation, their phenotype and precursor frequency, and provided evidence to suggest the involvement of DDOC as an alternative pathway during inflammation-induced osteoclastogenesis and bone loss. The new insight presented in this work provides impetus for further understanding of not only the physiological relevance and significance of DDOC development, but also the molecular mechanisms underlying this process during inflammatory bone disorders, with the ultimate goal of delineating the exact osteo-immune interactions driving inflammation-induced bone destruction, and developing novel therapeutic strategies in the future.flammation-induced osteoclastogensis is a well established osteo-immunological phenomenon associated with dys-regulated bone remodeling, whereby the frequency and activity of osteoclasts (OC) become elevated under inflammatory conditions, in response to several stimuli including osteogenic cytokines signaling. OC are bone-resorbing cells, thus considered to be central players during inflammation-induced bone loss. They are derived from precursors of the monocyte/ macrophage lineage, in response to receptor activator of NF-κB ligand (RANKL) and macrophage-colony stimulating factor (M-CSF). Inflammation-induced osteoclastogenesis can lead to irreversible bone destruction and physical disability, and may be the result of several factors including infections, metabolic bone disorders, or autoimmunity. Dendritic cells (DC) are innate immune effectors, and as antigen presenting cells, they are critically involved in regulating adaptive immune responses, including T-cell immunity. Additionally, DC share common progenitors with OC and infiltrate bone adjacent tissues during inflammation, where their interactions with T-cells constitute a key component of the inflammatory infiltrate at active disease sites in human and experimental rheumatoid arthritis and periodontitis. The work presented in this thesis is focused on the characterization of DC-derived OC (DDOC) development and phenotype, and the identification of the osteogenic factors required and/or involved during the regulation of this process. Our findings suggest that DC can viii act as OC precursors under inflammatory conditions, therefore indicating a possible direct contribution by DC to inflammation-induced osteoclastogenesis. In the presence of Aggregatibacter actinomycetemcomitans sonicates (Aa) [previously Actinobacillus], or protein antigens, some DC subset(s) were found to up-regulate OC phenotype and function in a RANKL/RANK-dependent manner. Additional work investigated the in vivo relevance of DDOC phenomenon and examined the role of the anti-inflammatory cytokine transforming growth factor-beta (TGF-β) in the regulation of RANKL-dependent DDOC development, and found TGF-β to be important both in vitro and in vivo. Collectively, this thesis has studied DDOC development and regulation, their phenotype and precursor frequency, and provided evidence to suggest the involvement of DDOC as an alternative pathway during inflammation-induced osteoclastogenesis and bone loss. The new insight presented in this work provides impetus for further understanding of not only the physiological relevance and significance of DDOC development, but also the molecular mechanisms underlying this process during inflammatory bone disorders, with the ultimate goal of delineating the exact osteo-immune interactions driving inflammation-induced bone destruction, and developing novel therapeutic strategies in the future

Higher Levels of Early Childhood Caries (ECC) Is Associated with Developing Psychomotor Deficiency: The Cross- Sectional Bi-Township Analysis for The New Hypothesis

The aim of this study was to reassess and confirm the relationship between early childhood caries (ECC) and manifestations of psychomotor deficiency in 4–6-yr-old kindergarteners, which has remained elusive to date. A cross-sectional study with bi-township analysis was designed whereby 353 kindergarteners, aged 4–6 whose caries were greater (dmft (decayed, missing and filled teeth, dmft index) = 5.25) than that of the national average, located in a rural township of central Taiwan were recruited using simple random-selection. Besides the personal, demographic, and dietary information, the measurements for caries and the amended comprehensive scales (CCDI) of children’s psychomotor development were used to address their relationship. One-way ANOVA vs. multiple linear regression were employed to compare the differences of variables between age, gender, BMI (Body Mass Index), and dmft scores vs. relationships among all variables, respectively. The results confirmed that there was a positive relationship between severe ECC (dmft > 3~8) and psychomotor deficiency (i.e., expressive language and comprehension-concept scales, etc.) amongst the kindergarteners analyzed. Our cross-sectional bi-township analysis has confirmed that there is indeed an association between severe ECC and psychomotor deficiency in kindergarteners, and we suggest that this may arise through critical stages of growth, not only via personal language communications, but psycho-social engagements as well. Therefore, a new hypothesis is proposed